Influence of Chronic Oral Infections on Senescence and Vascular Degeneration

慢性口腔感染对衰老和血管变性的影响

• 批准号: 239928725
• 负责人: Professorin Dr. Anette Melk, Ph.D.
• 金额: --
• 依托单位: Klinik für Zahnärztliche Prothetik und Biomedizinische Werkstoffkunde
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/239928725?language=en
• 关键词: Influence; Chronic; Oral; Infections; Senescence

Chronic oral inflammatory diseases like periodontitis have been shown to be linked to adverse cardiovascular outcomes. The underlying mechanism of this correlation is largely unknown. Senescence refers to a phenotype of permanent irreversible growth arrest described in mammalian cells in culture, and several lines of evidence point towards an important role of senescence in aging processes in vivo. The fact that advanced age is associated with poor periodontal health and an increased prevalence and severity of periodontitis leads us to hypothesize (1) that periodontitis induce cellular senescence locally in gingival epithelial cells and via the systemically detectable microinflammation in endothelial cells. The later is the relevant link for the pathogenesis of endothelial dysfunction and eventually structural vascular changes, (2) that preexisting senescence will not only lead to a higher susceptibility towards local infections, but also to more periodontitis-induced changes in vascular function, and (3) that , as a proof of concept, interventional strategies interfering with senescence, like the specific knowdown of p16INKa in endothelial cells, will lead to protection from those periodontitis-induced changes by increasing the regenerative potential. We will study the induction of senescence by oral bacteria or bacterial-challenged cells in vitro using gingival epithelial and umbilical endothelial cells to. To further explore the direct impact of periodontitis-induced senescence for the induction of cardiovascular changes, i.e. the development of atherosclerosis, we will perform in vivo studies. For this purpose, experimental periodontitis will be induced in Apolipoprotein E knockout mice (ApoE KO mice) that spontaneously develop atherosclerotic plaques. P. gingivalis-treated ApoE KO mice will be compared with untreated controls to prove that periodontitis accelerates senescence and leads to greater cardiovascular changes. The comparison of young and old mice will clarify, whether preexisting senescence leads to higher susceptibility towards periodontitis-induced vascular changes. We will then use ApoE KO mice with a specific p16INKa knockdown in endothelial cells to test whether these mice are protected from the vascular changes seen in P. gingivalis-treated ApoE KO mice. These later studies will be the proof of concept that interfering with senescence leads to an increased regenerative potential that in turn helps to counteract the vascular changes caused by a chronic inflammatory process. Apart from its importance for the process of periodontitis, this project has further implications by providing evidence for a causal relationship between chronic inflammatory processes and vascular degeneration through the induction of senescent changes.

慢性口腔炎性疾病如牙周炎已被证明与不良心血管结局有关。这种相关性的潜在机制在很大程度上尚不清楚。衰老是指在培养的哺乳动物细胞中描述的永久不可逆生长停滞的表型，并且几条证据指向衰老在体内衰老过程中的重要作用。高龄与牙周健康状况不佳以及牙周炎患病率和严重程度增加有关，这一事实使我们假设：（1）牙周炎通过全身可检测到的内皮细胞微炎症局部诱导牙龈上皮细胞衰老。后者是内皮功能障碍和最终结构血管变化的发病机制的相关联系，（2）预先存在的衰老不仅会导致对局部感染的更高易感性，而且还会导致更多牙周炎诱导的血管功能变化，以及（3）作为概念的证明，干预衰老的策略，就像内皮细胞中p16INKa的特异性降低一样，通过增加再生潜力，将导致对牙周炎诱导的变化的保护。我们将在体外使用牙龈上皮细胞和脐静脉内皮细胞研究口腔细菌或细菌攻击细胞对衰老的诱导作用。为了进一步探索牙周炎诱导的衰老对心血管变化（即动脉粥样硬化的发展）的直接影响，我们将进行体内研究。为此，将在自发发展动脉粥样硬化斑块的载脂蛋白E敲除小鼠（ApoE KO小鼠）中诱导实验性牙周炎。将牙龈卟啉单胞菌处理的ApoE KO小鼠与未处理的对照进行比较，以证明牙周炎加速衰老并导致更大的心血管变化。年轻和老年小鼠的比较将澄清，是否预先存在的衰老导致对牙周炎引起的血管变化的更高的易感性。然后，我们将使用内皮细胞中具有特异性p16INKa敲低的ApoE KO小鼠来测试这些小鼠是否免受牙龈卟啉单胞菌处理的ApoE KO小鼠中所见的血管变化的影响。这些后来的研究将是概念的证据，即干扰衰老导致再生潜力增加，从而有助于抵消慢性炎症过程引起的血管变化。除了其对牙周炎过程的重要性外，该项目还通过诱导衰老变化为慢性炎症过程和血管变性之间的因果关系提供了证据，从而具有进一步的意义。